JP2008521406A - 養子免疫療法のためのil−21の使用法および腫瘍抗原の同定法 - Google Patents
養子免疫療法のためのil−21の使用法および腫瘍抗原の同定法 Download PDFInfo
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Abstract
Description
サイトカインは通常、造血系の細胞の増殖もしくは分化を刺激し、または身体の免疫反応機構および炎症反応機構に関与する。インターロイキンは、免疫学的反応を媒介するサイトカインのファミリーである。免疫反応の中心は、多くのサイトカインを産生し、および抗原に対する適応免疫において役割を果たす、T細胞である。T細胞によって産生されるサイトカインは、1型および2型として分類されている(Kelso, A. Immun. Cell Biol. 76: 300-317, 1998(非特許文献1))。1型サイトカインは、IL-2、IFN-γ、LT-αを含み、ならびに炎症反応、ウイルス免疫、細胞内寄生虫免疫、および同種移植片拒絶に関与する。2型サイトカインは、IL-4、IL-5、IL-6、IL-10、およびIL-13を含み、ならびに液性反応、蠕虫免疫、およびアレルギー反応に関与する。1型と2型に共通のサイトカインには、IL-3、GM-CSF、およびTNF-αが含まれる。1型および2型を産生するT細胞集団は異なる種類の炎症組織に選択的に移動するということを示唆するある証拠がある。
ある局面において、本発明は、腫瘍抗原を同定するための方法であって、IL-21組成物および抗原提示細胞(APC)の存在下で、対象から単離された腫瘍物質を末梢血単核細胞(PBMC)と共培養する工程、培養物からT細胞集団を単離する工程、T細胞集団から個々のT細胞を濃縮する工程、ならびに抗原特異性についてT細胞クローンを特徴分析する工程を含む方法を提供する。ある態様において、濃縮とは個々のT細胞のクローニングである。
本発明を詳細に説明する前に、以下の用語を定義することがその理解に役立つ可能性がある。
ヒトIL-21(配列番号:1および配列番号:2)は、最初はzalpha11リガンドと表され、参照により本明細書に組み入れられる、同一出願人による米国特許第6,307,024号、および第6,686,178号に記載されている。IL-21受容体は、米国特許第6,057,128号に記載されている。以前はzalpha1J(配列番号:5および配列番号:6)と表された、IL-21受容体、ならびにヘテロダイマーの受容体であるIL-21R/IL-21Rγもまた、参照により本明細書に組み入れられる、同一出願人による米国特許第6,576,744号、第6,803,451号、第6,692,924号、および国際公開公報第00/17235号に記載されている。これらの刊行物に記載されているように、IL-21は、CD3について選別された、活性化ヒト末梢血細胞(hPBC)から作製されたcDNAライブラリーから単離された。CD3は、リンパ系起源の細胞、特にT細胞に特有の細胞表面マーカーである。
本発明は、抗原特異的ヒトCD8+ T細胞の1次反応の誘導におけるIL-21の正の調節的な役割が示された、ヒト健康ドナーおよびメラノーマ患者両方の研究に一部基づいている。正常な自己抗原を認識する希少ではあるが測定可能なナイーブT細胞集団を探知するために、IL-21存在下で、ペプチド-MHCテトラマーを使用すると、誘発され得る抗原特異的CD8 T細胞の頻度および絶対数が、IL-21非存在下で増殖させた培養と比べて、20倍よりも多く増加する。初期のプライミング期間中のIL-2、IL-7、またはIL-15の添加によって、サイトカインを与えられない培養を上回る付加的な効果がなかったので、抗原特異的T細胞反応の発生の増強は、このγ鎖受容体サイトカインに特異的である。IL-21に曝露され、および抗原によるプライミングを受けたT細胞は、IL-2およびIL-7などの、増殖を促進するサイトカインに反応する能力を保持し、ならびに容易に単離および拡大することができた。本発明は、抗原によって引き起こされるヘルパー非依存的IL-2産生、標的結合力の増強、および抗原特異的殺腫瘍の強化をもたらす、CD28アップレギュレーションおよび高親和性TCRの発現を特徴とする、IL-21によって増強されたヒト抗原特異的CD8+ T細胞の発生を提供する。本発明は、ヒト抗原特異的CD8+ T細胞反応の誘導および免疫療法、特に養子細胞療法のためのIL-21の使用法を提供する。
実施例1
A. 細胞株および試薬
メラノーマ細胞株A375(CRL 1619; American Type Culture Collection (ATCC), Manassas, VA)、およびMel 526(Arrighi et al., Cancer Res. 60 (16): 4446-52, 2000; Marcinola et al. J. Immunother Emphasis Tumor Immunol. 19 (3): 192-205, 1996)を、HEPES(25mM)、L-グルタミン(4mM)、ペニシリン(50U/ml)、ストレプトマイシン(50mg/ml)、ピルビン酸ナトリウム(10mM)、非必須アミノ酸(1mM)、および10%胎児ウシ血清(Hyclone, Utah)を含むRPMI中で維持した。両株ともHLA-A2アレルを発現しているが、Mel 526のみがMART-1抗原を発現している。T2細胞株は、HLA-A2アレルを発現するTAP欠損T-B細胞ハイブリッドである。EBV-LCL細胞株は、エプスタインバーウイルスにより形質転換されたリンパ芽球様細胞株である(Yee, FHCRC, Seattle, WA)。
メラノーマM26-35ペプチド特異的T細胞を作製した(Yee at al., PNAS 99: 16168, 2002; Yee et al., J. Immunol. 162: 2227, 1999; Tsai et al., J. Immunol. 158: 1796, 1997)。ドナーの血液は、Puget Sound Blood Center(Seattle, WA)のHLAタイピング研究室によってタイピングされた。まず、CD8+ T細胞をCD8陽性単離キット(Dynabeads, Dynal, Oslo, Norway)によって、白血球分離採血法で採血したPBMCから単離し、RPMI1640、25mM HEPES、2mM L-グルタミン、ペニシリン(50U/ml)、ストレプトマイシン(50mg/ml)(Life Technologies, Gaithersburg, MD)、および10%正常ドナー由来ヒト血清からなるCTL培地に懸濁し、その後、6ウェル組織培養皿(Costar, Corning Incorporated, Corning, NY)に6×106細胞/ウェルで置いた。成熟DCを採取し、室温で4時間、1%ヒト血清アルブミン(Life Technologies, Gaithersburg, MD)を含むPBS中の3μg/mlのβ2ミクログロビン(Scripps Lab, San Diego, CA)の存在下、2×106細胞/mlで、40μg/mlの合成ペプチドでパルスした。滅菌PBS(Life Technologies)で3回洗浄した後、純化したCD8 T細胞とDCを、6ウェルプレートに、3×105細胞/ウェルで混合した。培養を開始した直後に、サイトカイン、IL-15(10ng/ml, R&D Systems, Minneapolis, MN)、IL-2(10U/ml, Chiron, Emeryville, CA)、IL-7(10ng/ml, R&D Systems)、またはIL-21(30ng/ml, ZymoGenetics, Seattle, WA)、を各ウェルに個別に加えた。2回目の刺激の1日後、活性化した抗原特異的T細胞のさらなる拡大の促進のために、IL-2(50IU/ml)およびIL-7(10ng/ml)を加えた。
以前に記載されたプロトコル(Altman et al., Science 274: 94, 1996)に基づいて、Fred Hutchinson Cancer Center の免疫モニタリング研究室で、PEまたはAPC標識したM26-MHC-テトラマーおよびG154-MHC-テトラマーを作製した。試料分析用に、まず、25μlの2% FCS/PBS中の0.5×106細胞を、室温で1時間、ペプチドテトラマー-PEまたはAPC(20μg MHC/mlの最終濃度)で染色し、その後、4℃で20分間、抗CD28-APC(BD, PharMingen, San Diego, CA)または抗CD28-FITC(Caltac Lab, Burlingame, CA)、抗CCR7-PE、および抗CD45ROまたは抗CD45RA-FITC(BD, PharMingen, San Diego, CA)で染色した。PBSで洗浄した後、2%FBSを含むPBSに細胞を再懸濁し、DAPIを加えた。データを、FACScaliburフローサイトメーターおよびCellQuest(BD)を用いて取得し、ならびにFlowJoソフトウェア(Tree Star, San Carlos, CA)を用いて解析した。
磁気ビーズの組み合わせおよびAutomacs磁気分離装置(Miltenyi Biotech, Auburn California)の連続適用により、ヒト末梢血単核細胞からT細胞を純化した。CD8単離キットIIによる陰性選別を用いて、CD8+細胞を単離した。それに続くナイーブ(CD8+ CD45RO- CD45RA+ CD62L+)細胞の選別は、CD45ROビーズを用いたメモリーCD8細胞の除去、その後、PE結合CD62L抗体(BD, PharMingen, San Diego, CA)を用いた染色によるCD62L陽性細胞の陽性選別および抗PEビーズとのインキュベーションを伴った。メモリー細胞の単離(CD8+ CD45RA- CD45RO+)は、CD45RA+ビーズを用いたナイーブ集団の除去を伴った。FACsで評価した典型的な純度は95%を上回っていた。
Yee, 前記, 2002; Riddell et al., J. Immunolog. Methods 128: 189, 1990に記載されているようなクローニングおよび拡大の手順を用いて、T細胞を単離した。0.2mlのCTL培地に、抗CD3 mAb(OKT3, Ortho Tech, Raritan, NJ)および50U IL-2/mlと共に、1:50,000のレスポンダー 対 スティミュレーターの比率にした放射線照射フィーダー細胞(PBLおよびLCL)の存在下で、96ウェル丸底プレート(Nalge Nunc International, Denmark)にテトラマー+分離したT細胞を限界希釈でプレーティングした。プレーティング後10〜14日で、クローンの増殖について陽性のウェルを同定し、微小細胞毒性アッセイ法でスクリーニングした。ペプチド特異的クローンを25cm2フラスコ(Costar, Corning Incorporated, Corning, NY)に移し、抗CD3 mAbで再刺激し、かつ放射線照射した同種のPBLおよびLCLを速やかな拡大のためのフィーダー細胞として加えた。再刺激の24時間後、およびその後3日毎に、培養にIL-2を50U/mlで与えた。14日後、細胞をさらなる解析のために使用し、または凍結保存した。
標的細胞(375、526メラノーマ細胞株、またはT2細胞)を100μCi 51Crで標識し、および37℃+5% CO2で4時間、エフェクター細胞と共培養した。ペプチド量力価の検討のために、T2を101〜107pg/mlの範囲の濃度のペプチドで1時間パルスし、その後、51Cr標識の前に洗浄した。放出された51Crをγシンチレーションカウンターで測定し、以下の方程式を用いて、%特異的溶解を決めた:%特異的放出=実験的放出−自然放出/全放出。全てのアッセイ法において、自然放出は全放出の<10%であった。
CTLクローンを、室温で1時間、APC-テトラマー(20μg/ml)で染色し、結合していないテトラマーを除去するために、冷PBSで1回洗浄した。TCRからのそれらの解離の後、APC-テトラマーの再結合を防ぐために、過剰(100μg/ml)のPE標識テトラマーの存在下で、細胞をインキュベートした。この期間中、細胞のアリコートを異なる時点で回収し、かつフローサイトメトリー解析用に1%パラホルムアルデヒド中で固定した。APC テトラマーの解離の割合は、TCR親和性と逆相関した(Dutoit et al., J. Immunol. 168: 1167, 2002)。
IL-21は初回インビトロ刺激後に発生する抗原特異的CD8+ T細胞の頻度を強化する
HLA A2+健康ドナーのPBMCからCD8+ T細胞を単離し、かつ腫瘍関連自己抗原である、MART-1(M26-35ペプチド)の免疫原性エピトープでパルスした自己の成熟樹状細胞と共培養することにより、抗原特異的T細胞の初回インビトロ刺激についてのモデル系を確立した。サイトカインの添加なしで、またはIL-21を用いて、培養を増殖させた(図1)。刺激の7日後、テトラマー染色によって、培養におけるMART-1特異的CD8 T細胞反応の頻度を評価した。代表的な健康ドナー(CG、NE、およびLD)において、1サイクルのインビトロ刺激の後、サイトカインなしの対照培養と比べて、IL-21に曝露された培養では、16〜20倍のMART-1特異的CD8+ T細胞頻度の増加が観察された(それぞれ、0.12%対2.26%;0.12%対1.95%、および0.11%対2.2%)(図1)。IL-21処理した培養で発生した抗原特異的T細胞の絶対数は、対照培養を20〜30倍より多く上回った(表1)。
IL-21は主としてナイーブのCTL集団の中での抗原特異的T細胞反応を増強する
IL-21が抗原特異的CD8+ T細胞の発生を増強する能力を、ナイーブT細胞およびメモリーT細胞の中で別々に評価した。純化したナイーブ(CD45RA+、CD62L+が>98%)CD8+ T細胞の集団を、健常ドナー(CG)(図5)および転移性メラノーマのある個体(ST)の両方由来のメモリー(CD45RO+が100%)CD8+ T細胞と比較した。IL-21がメモリーCD8+ T細胞から発生するMART-1特異的細胞の頻度に最小限の効果を及ぼす(0.10%から0.15%へ、および0.05%から0.037%へ)のに対し、IL-21曝露の後、ナイーブCD8 T細胞の中では12〜90倍の増加が観察され(0.94%から12.5%へ、および0.08%から7.08%へ)、IL-21が主としてナイーブT細胞に影響を及ぼすという証拠を与えている。
IL-21処理した培養物から発生するCTLは増強された腫瘍反応性を有する高親和性の抗原特異的T細胞の集団を表す
IL-21の影響下、発生した抗原特異的T細胞集団の機能をクローンレベルでさらに特徴付けるために、健康ドナー(CG)およびメラノーマ患者(ST)の両方由来のテトラマー+ CD8+ T細胞を7日目に分離し、96ウェルプレートの中に限界希釈でクローニングした。微小細胞毒性アッセイ法によって同定したMART-1特異的クローンを拡大し、かつ1)ペプチドをパルスしたT2細胞の50%最大溶解に必要なペプチド濃度(P50)、および2)抗原陽性のメラノーマ標的を溶解する能力について検査した。P50を評価するために、HLA-A2をトランスフェクトしたEBV B細胞株、T2、を107〜102pMの範囲のペプチド濃度で滴定した。50%溶解(P50)のためのペプチド必要量(nM)として結果を示す。IL-21処理した培養物から発生したCTLクローンは、それらの未処理の等価物よりも>1ログ低いペプチド必要量が必要であった−それぞれ、平均3nM(0.6〜30nMの範囲) 対 平均80nM(16〜500nMの範囲)(図6A)。IL-21の同様の効果は、メラノーマ患者(ST)から発生したCTLクローンについても見られた(図6B)。
IL-21を用いた抗原特異的CD8 T細胞の培養はCD28発現、IFN-γおよびIL-2の産生を維持する
CD28はCD4 T細胞反応およびCD8 T細胞反応の両方の発生にとって重要な共刺激分子である。CD28受容体を介するシグナル伝達は、CD4 T細胞およびCD8 T細胞の両方におけるIL-2 mRNAの安定性の増加およびIL-2産生の増加をもたらす(Boise et al., Immunity 3: 87-98, 1995; Ragheb et al., J. Immunol. 163: 120-129, 1999)。活性化の後、CD28発現はヒトCD8+ T細胞のサブセットで失われ、および抗CD3刺激の後、このサブセットは増殖の減少を示す(Azuma et al., J. Immunol. 150: 1147-1159, 1993)。CD28-CD8+ T細胞は、高齢者、ならびに持続的ウイルス感染、EBVおよびCMVのある人々のCD8メモリーT細胞プールで増加している(Posnett et al., Int. Immunol. 11: 229-241, 1999)。CD28発現の消失はHIV患者において最も顕著であり(Appay et al., Nat. Med. 8: 379-385, 2002)、およびこの集団の増加はメラノーマのある患者で報告されている。最近、CMV特異的CD8 T細胞でCD28発現を回復することにより、インビトロでのIL-2産生および抗原特異的CD8 T細胞の生存の増加が維持されることが示された(Topp et al., J. Exp. Med. 198: 947-955, 2005)。したがって、この経路は、持続的なCD8の生存および機能のための重要な経路として認識されている。
IL-21はgp100およびNY-ESO-1抗原に対するCD8 T細胞反応に影響を及ぼす
T細胞がその他の自己抗原を認識することを示すために、その他2つの腫瘍関連自己抗原、メラノソーム抗原である、gp100(G154ペプチド)、および癌精巣抗原である、NY-ESO-1(NY157)を用いて、同様の方法で、CD8+ T細胞に対するIL-21の影響を評価した。Li et al., J. Immunol. 175: 2261-2269, 2005を参照されたい。
骨髄機能廃絶療法および養子細胞移植の後にIL-21を受けるメラノーマ患者における抗腫瘍免疫の増強
養子細胞療法(ACT)は、腫瘍反応性リンパ球のエクスビボ選択、および自己の腫瘍を有する宿主に対するその活性化に基づく。サイトカインの存在下、患者自身の腫瘍抗原の存在下で、腫瘍特異的T細胞(TIL)をインビトロで活性化および拡大し、その後、同じ患者に移し、その後、サイトカインによる維持治療を行う。非常に多くの患者で、これは、末梢における抗原特異的T細胞の数の増加を引き起こし、客観的な腫瘍反応によって見られるような抗腫瘍効果をもたらす。IL-21は、抗原特異的T細胞のインビトロ活性化剤/増量剤の両方として使用し、および癌患者に一度移されたT細胞の維持療法のためにも使用する。
IL-21を用いたインビトロ培養はACTのマウスモデルにおける抗腫瘍効果を増強する
Pmel-1トランスジェニックマウスは、ヒトメラノーマ特異的ペプチド抗原gp10025〜33に特異的なT細胞受容体(TCR)を発現するように人工的に作製されたマウスである(Overwijk et al., J. Exp. Med. 198: 569-580, 2003)。pmel-1トランスジェニックマウス由来の脾細胞を単離し、ならびに1μM ヒトgp10025〜33ペプチドおよび30IU/mlの組換えヒトIL-2または10〜100ng/mlのマウスIL-21を含む培地の存在下で、6〜7日間、培養した。
インビボでのIL−21処理はACTのマウスモデルにおける抗腫瘍効果を増強する
Pmel-1トランスジェニックマウスは、ヒトメラノーマ特異的ペプチド抗原gp10025〜33に特異的なT細胞受容体(TCR)を発現するように人工的に作製されたマウスである(Klebanoff et al., PNAS 101: 1969-1974, 2004)。pmel-1トランスジェニックマウス由来の脾細胞を単離し、ならびに1μM ヒトgp10025〜33ペプチドおよび30IU/mlの組換えヒトIL-2または10〜100ng/mlのマウスIL-21を含む培地の存在下で、6〜7日間、培養した。
Claims (16)
- 腫瘍抗原を同定するための方法であって、以下の工程を含む方法:
IL-21組成物および抗原提示細胞(APC)の存在下で、対象から単離された腫瘍物質を末梢血単核細胞(PBMC)と共培養する工程;
培養物からT細胞集団を単離する工程;
T細胞集団から個々のT細胞をクローニングする工程;ならびに
抗原特異性についてT細胞クローンを特徴分析する工程。 - T細胞集団が最終分化していないT細胞集団である、請求項1記載の方法。
- PBMCまたはT細胞集団が自己の細胞集団である、請求項1記載の方法。
- 腫瘍物質が全RNA、溶解した腫瘍細胞またはアポトーシス小体を含む、請求項1記載の方法。
- 単離されたT細胞集団がCD4+細胞を含まない、請求項2記載の方法。
- 共培養がIL-21組成物および1つまたは複数の追加のサイトカインの存在下である、請求項1記載の方法。
- 養子免疫療法で使用するためのT細胞集団を調製する方法であって、以下の工程を含む方法:
生物学的試料から末梢血単核細胞(PBMC)を単離する工程;
腫瘍を有する対象に対して組織適合性がある表現型を有するPBMCを同定する工程;
IL-21組成物およびAPCの存在下で、対象から単離された腫瘍物質をPBMCと共培養する工程;
細胞を培養で拡大する工程;ならびに
細胞を再導入して対象に戻す工程。 - PBMCが自己である、請求項7記載の方法。
- 腫瘍物質をT細胞集団と共培養する工程の後に、T細胞を濃縮する、請求項7記載の方法。
- 養子免疫療法で使用するためのT細胞集団を調製する方法であって、以下の工程を含む方法:
T細胞を含む生物学的試料を単離する工程;
腫瘍を有する対象に対して組織適合性がある表現型を有するT細胞集団を同定する工程;
IL-21組成物およびAPCの存在下で、対象由来の腫瘍物質をT細胞集団と共培養する工程;
これらの細胞を培養で拡大する工程;ならびに
これらの細胞を対象に再導入して戻す工程。 - T細胞集団が自己である、請求項10記載の方法。
- 腫瘍物質が全RNA、溶解した腫瘍細胞、もしくはアポトーシス小体を含む、請求項7または10記載の方法。
- T細胞集団がナイーブであるか、または最終分化していない、請求項10記載の方法。
- 腫瘍物質をT細胞集団と共培養する工程の後に、T細胞を濃縮する、請求項10記載の方法。
- 抗原特異的な細胞傷害性T細胞のエクスビボ増幅のための方法であって、以下の工程を含む方法:
T細胞を含む生物学的試料を単離する工程;
対象に対して組織適合性がある表現型を有するT細胞集団を同定する工程;
IL-21組成物の存在下で、対象由来の抗原性物質をT細胞集団と共培養する工程;
細胞を培養で拡大する工程;および
細胞を対象に再導入して戻す工程。 - 腫瘍物質をT細胞集団と共培養する工程の後に、T細胞を濃縮する、請求項15記載の方法。
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US63072704P | 2004-11-24 | 2004-11-24 | |
PCT/US2005/042782 WO2006065495A2 (en) | 2004-11-24 | 2005-11-23 | Methods of using il-21 for adoptive immunotherapy and identification of tumor antigens |
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US (5) | US20060269973A1 (ja) |
EP (1) | EP1814580B1 (ja) |
JP (1) | JP2008521406A (ja) |
CA (1) | CA2587136A1 (ja) |
CY (1) | CY1122390T1 (ja) |
DK (1) | DK1814580T3 (ja) |
ES (1) | ES2601896T3 (ja) |
HU (1) | HUE030210T2 (ja) |
LT (1) | LT1814580T (ja) |
PL (1) | PL1814580T3 (ja) |
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US20150023938A1 (en) | 2015-01-22 |
LT1814580T (lt) | 2016-12-12 |
US9951310B2 (en) | 2018-04-24 |
CA2587136A1 (en) | 2006-06-22 |
ES2601896T3 (es) | 2017-02-16 |
US20190316088A1 (en) | 2019-10-17 |
HUE030210T2 (en) | 2017-04-28 |
EP1814580A2 (en) | 2007-08-08 |
PT1814580T (pt) | 2016-11-11 |
WO2006065495A3 (en) | 2006-09-08 |
WO2006065495A2 (en) | 2006-06-22 |
US11306289B2 (en) | 2022-04-19 |
EP1814580B1 (en) | 2016-08-10 |
US20220204933A1 (en) | 2022-06-30 |
DK1814580T3 (en) | 2016-12-12 |
PL1814580T3 (pl) | 2017-03-31 |
CY1122390T1 (el) | 2020-07-31 |
US20060269973A1 (en) | 2006-11-30 |
US20100310533A1 (en) | 2010-12-09 |
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